Tertiary amino derivatives of dihydro-anthracene



Patented July 16, 1946 TERTIARY AMINO DERIVATIVES F- DIHYDRO-ANTHRACENE John W. Cusic, Skokie, Ill., assignor to G. D.

Searle & (30.. Skokie, 111., a corporation 0111'- linois' No. Drawing Original application October 7,.

I943, S'erialNo. 505,355. Dividecl'and this amflication: May 12, 1945, Serial No. 593,541

This invention relates to new compositions of matter which maybe advantageously used as antispasmodic agents. More particularly, the invention relates to new compositions of matter which are tertiary aminoderivatives of dihydro- I anthracene. These new compounds may be represented by the formulae:

CH2 CH2 o and CH C 5H NRR I OHrC1\12 Gib-CH2 ment of the R group to the first carbon in the side chain. These compounds have been tested and found to be powerful and useful antispas modic agents. Only the compounds represented by Formula II above are claimed in this application; the compounds represented by Formula I are claimed in applicant's original application,

. Serial No. 505,355, filed October '7, 1943, of which the present application is a division.

The prior art has disclosed several different categories of synthetic antispasmodic agents, most of which, however, have been characterized by the presence of some functional group (as, for instance, an ester group) in addition to the tertiary amine group in the molecule. Blicke (Journal of American Chemical Society, volume 61, pages 91 and 771) has disclosed a series of tertiary amines, free of other functional groups, some of which are stated to be active as antispasmodic agents. However, those stated to be active are invariably characterized by the presence of two aralkyl or hydrogenated aralkyl groups attached to the nitrogen atom; conversely, those which contained two simple alkyl groups On the nitrogen atom (as in the present invention) were all stated to be inactive. The antispasmodic agents of this invention thus notably differ from those disclosed as active by Blicke in that they have the one aralkyl group characterized by the dihydroanthracene nucleus,

2 Claims. (01. 260,-29 3) or that the aliphatic ring. a

I havefound that the compositions of the present inventionmay be conveniently prepared by the interaction of an alkali metal derivative of dihydroanthracene with an appropriate dialkylaminoalkyl halide or N-methyl-i-halogene piperidine. The following is a detailed example of such preparation: 1

Example V A solution of butyl lithium in dry ether is prepared in the usual manner from 27.4 grams of n-butyl bromide and 2.8 grams of lithium. This solution is added gradually to a solution or suspension of 18.0 grams of dihydroanthracene in dry ether, and the resulting solution refluxed for about two hours. The whole operation is preferably conducted under an atmosphere of nitrogen. At the end of this time, 15 grams of 'y-diethylaminopropy1 chloride are added, and the resultant mixture stirred for twelve hours or more without heating. A small amount of alcohol is added to decompose any unreacted organometallic compounds, andthe reaction mixture is extracted with dilute hydrochloric acid. The

acid extract is made alkaline, and the free base recovered by ether extraction of this alkaline liquor and subsequent evaporation of the ether. It is an oil which can readily be purified by vacuum distillation; it boils at 173 -175 centigrade at 6 millimetres of pressure.

The free base readily forms salts with acids, most of which are solid, crystalline compounds which are more convenient to handle for use as nedicinals. Further, the salts are in general readily soluble in water, whereas thefree base is quite insoluble in water. These salts may be obtained by neutralizing a solution of the base in dry ether with an absolute alcoholic solution of the desired acid. Thus, the hydrochloride was obtained as a crystalline compound which melts at 181-183 centigrade.

The above example is merely illustrative; use of other aminoalkyl halides or of 4-halogen-N- alkylpiperidines in the same procedure will yield the corresponding amines and salts thereof. Among other compounds, I have thus prepared the p-diethylaminoethyl, the c-dibutylaminoethyl, the ,B-diethylaminopropyl and the N-methyl-piperidyl-4-derivatives of 9,10-dihydroanthracene, together with their hydrochlorides and other salts.

In determining the utility of these substances as antispasmodic agents, I have found that nitrogen is itself a part: ot a cycloa 9- (p-diethylaminoethyl) -9, IO-dihydroanthracene hydrochloride is a preferred compound. Illustrative of its utility as an antispasmodic agent is the fact that, when tested on isolated strips 01. rabbit intestine or uterus, it has shown a powerful relaxing effect; both on untreated muscle and on muscle which had previously been stimulated by a drug such as acetylcholine or histamine. Quan j f titatively, its potency equals or surpasses thatof V such drugs as the diethylaminoethyl: esters oi fluorene-9-carboxylic acid or of diphenylacetic acid, both of which are finding acceptance among the medical professions in-thi's country,:and ap- 7 1 3 proaches that of atropine.

The 'y-diethylaminopropy1 Y derivative 7 v was shown to be approximately as potent as the abovecited compound in similar tests. otherswill vary" I among themselves somewhat, but all constitute I a group of powerful antispasmodic drugs. They also vary somewhat among themselves in toxicity,

but in each case theitoXic dose is greatly in excess of the therapeutically effective dose; s0' that these compounds may be safely'administered to man or animals ,-in effective doses without untoward side effects- It is tobe understood that the amino compounds referred to .in theflappended, claims are intendedto refer .to the bases describedtherein; whether they be in the form .of the free base or of a salt with a non-toxic acid.

I claim: 1. New compositions of matter comprising tel! tiary amines of the formula:

as NR wherein R represents an alkyl group containing not more than four carbon atoms.

2. A new composition of matter comprising 9 (N=methylpiperidyl-4) -9, 10- dihydroanthracene of the formula;

c s f 

